Critically ill premature infants in neonatal ICUs are severely stressed and undergo numerous painful procedures, so they are often treated with narcotics such as morphine to try and relieve their stress and pain responses-sometimes for weeks or months. This is an important health care issue for two reasons: 1) neonatal stress/pain is believed to have long-term adverse effects on the developing brain, including behavioral disorders such as depression and addiction; and 2) there are also concerns about the neurodevelopmental effects of prolonged narcotic exposure used to try and ameliorate neonatal stress/pain responses. This exploratory grant application is written in response to RFA-DA-06-005 "Prescription Opioid Use and Abuse in the Treatment of Pain." For these studies, we have developed a unique mouse model of preterm neonatal pain/stress and narcotic exposure which mimics the clinical condition of critically ill preterm infants in the neonatal ICU. We have also developed a new collaboration between our developmental neuropharmacology group and the Chavkin lab-which is focused on understanding mechanisms for the effects of pain/stress on adult addiction/reward behavior. The overall objective of our application is to use our unique mouse model to improve our understanding of the long-term effects of neonatal stress and chronic narcotic exposure on adult addictive behavior, and to explore mechanisms for these long-term effects. Our central hypothesis is that repeated neonatal pain/stress induces release of endogenous dynorphin peptides which persistently activates kappa opioid receptors which causes a subsequent sensitization to the rewarding properties of narcotics experienced later in life. Further, we hypothesize that neonatal morphine treatment ameliorates these long-term effects of neonatal pain/stress on adult addictive and depressive behavior by decreasing the neonatal release of endogenous dynorphin. We will address the following Specific Aims: 1. To examine long-term, gender-specific effects of neonatal pain/stress, with or without morphine treatment, on adult addictive and depressive behavior; 2. Using prodynorphin and kappa opioid receptor knockout mice, we will test our central hypothesis regarding potential mechanisms for the long-term effects of neonatal pain/stress and its treatment on adult addictive and depressive behaviors. Understanding the long-term effects of neonatal stress and narcotics on adult addictive and depressive behaviors will help clinicians who manage these vulnerable infants to care for them more safely and effectively. [unreadable] [unreadable] [unreadable]